Following recent technological developments and the rapid evolution in our understanding of the epigenome, the structure of genomic DNA, studies of the role of the aging brain's epigenome in Alzheimer's disease (AD) have recently emerged. In our first funding cycle, we profiled DNA methylation and a histone mark (H3K9Ac) in the dorsolateral prefrontal cortex (DLPFC) of more than 700 older subjects from two prospective clinical-pathologic cohort studies. Given the depth of ante- and post-mortem phenotyping, we made important advances in our understanding of the aging brains' epigenome: amyloid and tau pathologies, the hallmarks of AD, have profound but distinct and reproducible effects on the epigenome. These associations occur throughout the genome. Although independent of the effects of genetic variants associated with AD susceptibility, the epigenomic changes integrate into a genetically-defined AD susceptibility network and may be involved in disease susceptibility. In this application, we propose to use a new experimental approach, ATACseq, which provides a comprehensive, genome-wide profile of active chromatin, to generate cell-type specific profiles, targeting cortical neurons implicated in both amyloid and tau pathology by our earlier studies as well as microglia/macrophages whose role in AD susceptibility was highlighted by genetic studies and our methylome analyses. Our proposal leverages an extensive experimental research infrastructure, benefits from an experienced analytic team applying cutting-edge methods, and contributes to the AD research community by delivering both a more comprehensive evaluation of epigenomes in the original collection of ~700 brains and new epigenomic and transcriptomic data in an additional 500 brains. Further, application of causal inference techniques will generate network models for each cell type and identify regulator genes that we will both validate and target with compound discovery in the translational component of the application. Thus, we propose to uncover fundamental mechanisms of the epigenome that contribute to AD and to begin to identify targets that can be manipulated in drug discovery efforts.